This invention discloses and claims novel intermediates and procedures for the synthesis of camptothecin derivatives, such as irinotecan, and other compounds related to the synthesis of CPT- 11. Related procedures and compounds are also disclosed, such as a novel method of making mappicine.
The compound given the label 14CPT in this document is mentioned in M. Shamma, D. A. Smithers, V. St. George, Tetrahedron, 1973, 1949-1954.
The asymmetric synthesis of this compound, 14 CPT, is reported in the following documents (grouped by author):
Group 1.
H. Terasawa, M. Sugimori, A. Ejima, H. Tagawa, Chem. Pharm. Bull., 1989, 37, 3382-3385.
A. Ejima, H. Terasawa, M. Sugimori, H. Tagawa, J. C. S. Perkin I, 1990, 27-31.
H. Tagawa, H. Terasawa, A. Ejima, U.S. Pat. No. 4,778,891 (Oct. 18, 1988).
H. Tagawa, H. Terasawa, A. Ejima, E P 220601 (Oct 14, 1986).
Group 2.
M. C. Wani, A. W. Nicholas, M. E. Wall, J. Med. Chem. 1987, 2317-2319.
M. C. Wani, A. W. Nicholas, M. E. Wall, U.S. Pat. No. 5,053,512 (Oct 1, 1990).
M. E. Wall, M. C. Wani, A. W. Nicholas, G. Manikumar, U.S. Pat. No. 4,894,456 (Jan. 16, 1990).
M. E Wall, M. C. Wani, A. W. Nicholas, and G. Manikumar, WO 90/03169 (Sep. 28, 1988).
Camptothecin derivatives, such as irinotecan, are effective anticancer drugs. This invention describes an efficient method of synthetic synthesis for a variety of camptothecin derivatives, including irinotecan or CPT-11, and other useful compounds like mappicine.
This invention comprises compounds, processes, reactions and reagents as shown in the CHARTS, formulas and figures herein. The compounds, processes, reactions and reagents are useful for the manufacture of camptothecin derivatives such as CPT-11 and other related compounds such as mappicine.
Specific compounds selected from the compounds described and labeled in the specification are the compounds in the CHARTS labeled 2G, 3G, 4G, 5G, 6G, 7GG, 7GA, 8GG, 8GA, 8GB, 9GG, 9GA, 10G, 10G(S), 10G(R), 11G, 11G(S), 11G(R), 12GA-1, 12GA-1(S), 12GA-1(R), 12GA-2, 12GA-2(S), 12GA-2(R), 12GB-1, 12GB-1(S), 12GB-1(R), 12GB-2, 12GB-2(S), 12GB-2(R), 12G, 12G(S), 12G(R), 13G, 13G(S), or 13G(R),
where R1 is any optionally substituted C1-8 alkyl, including lower alkyl, C3-10 cycloalkyl, lower alkyl-C3-10 cycloalkyl, alkenyl, aryl, substituted aryl, alkylaryl, or substituted alkylaryl, including benzyl and substituted benzyl;
where R2 is H,
a) any optionally substituted alkyl, including C1-8alkyl, alkylaryl, including C1-6alkyl-aryl, C1-8alkyl-C6aryl, substituted benzyl and unsubstituted benzyl;
b) xe2x80x94C(O)xe2x80x94R3, or
c) xe2x80x94C(R7)2xe2x80x94Oxe2x80x94R3 where each R7 is independent of the other;
where R3 is H, optionally substituted C1-8 alkyl, including lower alkyl, cycloalkyl, alkenyl, aryl, substituted aryl, and alkylaryl, or substituted alkylaryl, including benzyl and substituted benzyl;
where R4 is H, optionally substituted C1-8 alkyl, including lower alkyl, C3-10 cycloalkyl, lower alkyl-C3-10 cycloalkyl, alkenyl, aryl, substituted aryl, alkylaryl, or substituted alkylaryl, including benzyl and substituted benzyl;
where R5 is H, optionally substituted C1-8 alkyl, including lower alkyl, aryl, substituted aryl, or two R5 groups may be combined to form cyclopentane or cyclohexane, or substituted derivatives thereof;
where R6is optionally substituted C1-8 alkyl, lower alkyl, including ethyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, including benzyl and substituted benzyl, C3-10 cycloalkyl, lower alkyl-C3-10 cycloalkyl, heteroaryl, or substituted heteroaryl,
where R7 is independently H, optionally substituted C1-8 alkyl, including lower alkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, or two R7 groups may be combined to form cyclopentane or cyclohexane or substituted derivatives thereof.
where R8 is optionally substituted C1-6 alkyl, including lower alkyl, including t-butyl, C3-10 cycloalkyl, lower alkyl-C3-10 cycloalkyl, alkenyl, aryl, substituted aryl, alkylaryl, or substituted alkylaryl, including benzyl and substituted benzyl.
Other specific compounds of the invention are selected from the compounds described and labeled in the specification are 2CPT, 3CPT, 4CPT, 5CPT, 6CPT, 7CPT, 7CPTA, 8CPTG, 8CPTA, 8CPTAB, 9CPTG, 9CPTA, 9CPTB, 10CPT, 10CPT(S), 10CPT(R), 11CPT, 11CPT(S), 11CPT(R), 12CPTA-1, 12CPTA-1(S), 12CPTA-1(R), 12CPTA-2, 12CPTA-2(S), 12CPTA-2(R), 12CPTB-1, 12CPTB-1(S), 12CPTB-1(R), 12CPTB-2, 12CPTB-2(S), 12CPTB-2(R), 12CPT, 12CPT(S), 12CPT(R), 13CPT, 13CPT(S), and 13CPT(R) where R1-R9 is defined above.
Other specific compounds of the invention are selected from the compounds described and labeled in the specification as 6MG, 7MG, 8MG, 9MG, 10MG, 11MG,12MG,13MG, except where 13MG has an R6 that is C1-2 alkyl, where the variables have the same definition as the variables above.
Other specific compounds of the invention are selected from the compounds described and labeled in the specification as 5MM, 6MM, 7MM, 8MM, 9MM, 10MM, 11MM, or 12MM.
In addition to the compounds, various procedures labeled as STEPS are also described and claimed in this invention. Those STEPS include the STEPS described and labeled in the specification as CHART G comprising; STEP 2, or STEP 3, or STEP 4, or STEP 5, or STEP 5a, or STEP 5b, or STEP 6, or STEP 7GG, or STEP 7GA, or STEP 8GG, or STEP 8GA, or STEP 8GB, or STEP 9GG, or STEP 9GA, or STEP 9GB, or STEP 10GG, or STEP 10GA, or STEP 10 Resolution, or STEP 11, or STEPS 12, or STEP 13, or STEP 14 or any combination thereof combining two or more STEPS.
Also described and claimed are those STEPS described and labeled in the specification as CHART CPT comprising; STEP 7G, or STEP 7A, or STEP 8G, or STEP 8A, or STEP 8B, or STEP 9G, or STEP 9A, or STEP 9B, or STEP 10G, or STEP 10A, or STEP 11, or STEP 12, or STEP 13, or STEP 14 or any combination thereof combining two or more STEPS.
Also described and claimed are those STEPS described and labeled in the specification as CHART M-G comprising; STEP 5, or STEP 6, or STEP 7, or STEP 8 or STEP 9, or STEP 10, or STEP 11, or STEP 12, or STEP 13, or any combination thereof combining two or more STEPS.
Also described and claimed are those STEPS described and labeled in the specification as CHART M-M comprising; STEP 5, or STEP 6, or STEP 7, or STEP 8 or STEP 9, or STEP 10, or STEP 11, or STEP 12, or STEP 13, or any combination thereof combining two or more STEPS.